Sensitivity to cigarette smoke-induced COPD is highly variable. Many genetic and environmental factorsthat are thought to be responsible for this natural variation, however, remain unidentified. Our preliminaryresults suggest that the level of elastin in the lung is critical for normal lung development and for timely andefficient repair following injury. When elastin levels are below a critical threshold, repair is unproductive andthe lungs are more prone to develop COPD. Moreover, we have found that patients with mutations in theelastin gene (ELN) develop severe, very early onset bronchiectasis, emphysema and end-stage lungdisease. Rare variants of elastin could also predispose to enhanced lung damage by affecting the quality ofthe elastic fiber. In this case, minor alterations in elastin processing or assembly could support normal lungdevelopment and function but result in fibers that have increased susceptibility to degradation by proteases.The central hypothesis of this proposal is that the quality and quantity of pulmonary elastin is a criticalfactor in determining susceptibility to cigarette smoke-induced lung damage, leading to COPD. Thishypothesis is supported by preliminary data indicating that both quantitative and qualitative deficiency inelastin can predispose to smoke-induced emphysema in both animal models and in inherited syndromes inhumans caused by ELN mutations. The goal of this proposal is to uncover the mechanisms by which elastindefects result in COPD, and to assess mutations and variants in ELN as risk factors of COPD. To achievethese goals we propose the following specific aims:
Aim 1. To test if human genetic diseases caused bymutations in ELN are associated with an increased risk of COPD.
Aim 2. To test whether genetic variantspresent in the normal population (a) alter ELN function and (b) are associated with quantitative outcomemeasures in patients with severe emphysema.
Aim 3 : To test if lower than normal levels of lung elastinresulting from genetic or environmental factors lead to increased susceptibility to COPD.
Aim 4. To test ifqualitative alterations in pulmonary elastin arising from rare elastin variants contribute to COPDsusceptibility.
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